Recent studies estimate that most human cancers result from modifiable lifestyle factors, including diet. Lowering exposure to heterocyclic amines (HAs), which are formed in cooked meats, is an obtainable goal that may have a real impact on cancer incidence. This proposal addresses: 1) safe cooking methods that reduce HA formation, 2) identifying unknown mutagens and establishing their potency, 3) understanding the influence of other foods on reducing human HA absorption, 4) mechanistic studies of inhibition of flavonoids and 5) establishing the relationship between dietary questionnaires and HAs in urine. Meat cooking will be investigated to understand the conditions that reduce the formation of heterocyclic amines while using microbiology to monitor food safety. New, unknown mutagens will be isolated from beef and their amounts determined in a survey of well-cooked foods. Additionally, the parameters responsible for high mutagenic potency in new and existing HAs will be investigated as structure/activity relationships. Since there is human exposure to HAs, we can now investigate HA-diet interactions in individuals via the analysis of urinary metabolites. Exploratory studies will determine if parsley, green tea, and fiber, each shown to be preventative in epidemiology studies, can affect the total human uptake and metabolism of one HA, PhIP. Enticing results in reducing mutations with the flavonoid apigenin compel us to investigate structure/inhibition relationships experimentally and with a computational model. To quantify the dietary dose of heterocyclic amines in the population and in individuals, HA biomarkers will be developed and related to dietary questionnaires that account for diverse cooking practices. In all, this interdisciplinary research to reduce exposure combines toxicology with analytical chemistry, computational chemistry and physics to investigate heterocyclic amines and human cancer etiology.